Carbonic anhydrases in meningiomas: association of endothelial carbonic anhydrase II with aggressive tumor features

Laboratory investigation

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  • 1 Orton Orthopaedic Hospital, Invalid Foundation, Helsinki;
  • | 2 Department of Neurology and
  • | 3 Unit of Neurosurgery, Tampere University Hospital, Tampere, Finland;
  • | 4 Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic;
  • | 5 Institute of Medical Technology and School of Medicine, University of Tampere and Tampere University Hospital; and
  • | 6 Department of Pathology, Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland
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Object

Carbonic anhydrase (CA) II and IX are enzymes involved in pH homeostasis and have been shown to be upregulated in several types of cancer. In this study, the authors evaluate the expression of CA II and IX in meningiomas and assess their relationship to patient age, tumor type and grade, tumor sex hormone receptor status, tumor cell proliferation, and tumor recurrence.

Methods

This study was conducted in consecutive patients who underwent meningioma surgeries at Tampere University Hospital between 1989 and 1999. The expression of CA II and IX was studied immunohistochemically using a tissue microarray technique and specific antibodies.

Results

Immunohistological staining with CA II and IX was assessed in 443 primary and 67 recurrent tumor specimens. Of these samples, 455 were benign (WHO Grade I), 49 atypical (Grade II), and 6 malignant (Grade III). Endothelial cells in 14.8% of the tumors stained positively for CA II. Tumor cells were positive for CA IX in 11.6% of the cases. Endothelial CA II expression correlated with increasing histological grade (p = 0.002), and tumor proliferation rates were higher in CA II+ versus CA II− cases (p = 0.002). Androgen receptor–negative tumors were found to be CA II+ significantly more often than androgen receptor–positive tumors (p = 0.001). No associations were found with the CA IX enzyme.

Conclusions

Carbonic anhydrase II positivity in the endothelium was associated with cell proliferation and malignancy grade. These results suggest that CA II expression is associated with malignant progression of meningiomas and could thus be a target molecule for anticancer therapy.

Abbreviations used in this paper:

AR = androgen receptor; CA = carbonic anhydrase; DAB = 3,3′-diaminobenzidine tetrahydrochloride; PI = proliferation index; TBST = Tris-buffered saline Tween-20.

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  • 1

    Beasley NJ, , Wykoff CC, , Watson PH, , Leek R, , Turley H, & Gatter K, et al.: Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res 61:52625267, 2001

    • Search Google Scholar
    • Export Citation
  • 2

    Bekku S, , Mochizuki H, , Yamamoto T, , Ueno H, , Takayama E, & Tadakuma T: Expression of carbonic anhydrase I or II and correlation to clinical aspects of colorectal cancer. Hepato-gastroenterology 47:9981001, 2000

    • Search Google Scholar
    • Export Citation
  • 3

    Brennan DJ, , Jirstrom K, , Kronblad A, , Millikan RC, , Landberg G, & Duffy MJ, et al.: CA IX is independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res 12:64216431, 2006

    • Search Google Scholar
    • Export Citation
  • 4

    Brizel DM, , Scully SP, , Harrelson JM, , Layfield LJ, , Bean JM, & Prosnitz LR, et al.: Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56:941943, 1996

    • Search Google Scholar
    • Export Citation
  • 5

    Chia SK, , Wykoff CC, , Watson PH, , Han C, , Leek RD, & Pastorek J, et al.: Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19:36603668, 2001

    • Search Google Scholar
    • Export Citation
  • 6

    Chiang WL, , Chu SC, , Yang SS, , Li MC, , Lai JC, & Yang SF, et al.: The aberrant expression of cytosolic carbonic anhydrase and its clinical significance in human non-small cell lung cancer. Cancer Lett 188:199205, 2002

    • Search Google Scholar
    • Export Citation
  • 7

    Giatromanolaki A, , Koukourakis MI, , Sivridis E, , Pastorek J, , Wykoff CC, & Gatter KC, et al.: Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 61:79927998, 2001

    • Search Google Scholar
    • Export Citation
  • 8

    Haapasalo J, , Nordfors K, , Järvelä S, , Bragge H, , Rantala I, & Parkkila AK, et al.: Carbonic anhydrase II in the endothelium of glial tumors: a potential target for therapy. Neuro Oncol 3:308313, 2007

    • Search Google Scholar
    • Export Citation
  • 9

    Haapasalo JA, , Nordfors KM, , Hilvo M, , Rantala IJ, , Soini Y, & Parkkila AK, et al.: Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 12:473477, 2006

    • Search Google Scholar
    • Export Citation
  • 10

    Harkonen PL, , Makela SI, , Valve EM, , Karhukorpi EK, & Vaananen HK: Differential regulation of carbonic anhydrase II by androgen and estrogen in dorsal and lateral prostate of the rat. Endocrinology 128:32193227, 1991

    • Search Google Scholar
    • Export Citation
  • 11

    Hockel M, , Schlenger K, , Mitze M, , Schaffer U, & Vaupel P: Hypoxia and Radiation Response in Human Tumors. Semin Radiat Oncol 6:39, 1996

  • 12

    Hussain SA, , Palmer DH, , Ganesan R, , Hiller L, , Gregory J, & Murray PG, et al.: Carbonic anhydrase IX, a marker of hypoxia: correlation with clinical outcome in transitional cell carcinoma of the bladder. Oncol Rep 11:10051010, 2004

    • Search Google Scholar
    • Export Citation
  • 13

    Hynninen P, , Vaskivuo L, , Saarnio J, , Haapasalo H, , Kivelä J, & Pastorekova S, et al.: Expression of transmembrane carbonic anhydrases IX and XII in ovarian tumors. Histopathology 49:594602, 2006

    • Search Google Scholar
    • Export Citation
  • 14

    Härkönen PL, & Väänänen HK: Androgen regulation of carbonic anhydrase II, a major soluble protein in rat lateral prostate tissue. Biol Reprod 38:377384, 1988

    • Search Google Scholar
    • Export Citation
  • 15

    Ivanov S, , Liao SY, , Ivanova A, , Danilkovitch-Miagkova A, , Tarasova N, & Weirich G, et al.: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905919, 2001

    • Search Google Scholar
    • Export Citation
  • 16

    Kleihues P, , Louis DN, , Scheithauer BW, , Rorke LB, , Reifenberger G, & Burger PC, et al.: The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 61:215219, 2002

    • Search Google Scholar
    • Export Citation
  • 17

    Kononen J, , Bubendorf L, , Kallioniemi A, , Barlund M, , Schraml P, & Leighton S, et al.: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844847, 1998

    • Search Google Scholar
    • Export Citation
  • 18

    Korhonen K, , Salminen T, , Raitanen J, , Auvinen A, , Isola J, & Haapasalo H: Female predominance in meningiomas can not be explained by differences in progesterone, estrogen, or androgen receptor expression. J Neurooncol 80:17, 2006

    • Search Google Scholar
    • Export Citation
  • 19

    Leppilampi M, , Koistinen P, , Savolainen ER, , Hannuksela J, , Parkkila AK, & Niemela O, et al.: The expression of carbonic anhydrase II in hematological malignancies. Clin Cancer Res 8:22402245, 2002

    • Search Google Scholar
    • Export Citation
  • 20

    Liao SY, , Brewer C, , Zavada J, , Pastorek J, , Pastorekova S, & Manetta A, et al.: Identification of the MN antigen as a diagnostic biomarker of cervical intraepithelial squamous and glandular neoplasia and cervical carcinomas. Am J Pathol 145:598609, 1994

    • Search Google Scholar
    • Export Citation
  • 21

    Loncaster JA, , Harris AL, , Davidson SE, , Logue JP, , Hunter RD, & Wycoff CC, et al.: Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61:63946399, 2001

    • Search Google Scholar
    • Export Citation
  • 22

    Marks SM, , Whitewell HL, & Lye RH: Recurrence of meningiomas after operation. Surg Neurol 25:436440, 1986

  • 23

    McKiernan JM, , Buttyan R, , Bander NH, , Stifelman MD, , Katz AE, & Chen MW, et al.: Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma. Cancer Res 57:23622365, 1997

    • Search Google Scholar
    • Export Citation
  • 24

    Olive PL, , Aquino-Parsons C, , MacPhail SH, , Liao SY, , Raleigh JA, & Lerman MI, et al.: Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res 61:89248929, 2001

    • Search Google Scholar
    • Export Citation
  • 25

    Parkkila AK, , Herva R, , Parkkila S, & Rajaniemi H: Immunohistochemical demonstration of human carbonic anhydrase isoenzyme II in brain tumours. Histochem J 27:974982, 1995

    • Search Google Scholar
    • Export Citation
  • 26

    Parkkila AK, , Parkkila S, & Rajaniemi H: Carbonic anhydrase isoenzymes II and I are present in the zona glomerulosa cells of the human adrenal gland. Histochemistry 99:3741, 1993

    • Search Google Scholar
    • Export Citation
  • 27

    Parkkila S, , Parkkila AK, , Juvonen T, , Lehto VP, & Rajaniemi H: Immunohistochemical demonstration of the carbonic anhydrase isoenzymes I and II in pancreatic tumours. Histochem J 27:133138, 1995

    • Search Google Scholar
    • Export Citation
  • 28

    Parkkila S, , Rajaniemi H, , Parkkila AK, , Kivela J, , Waheed A, & Pastorekova S, et al.: Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A 97:22202224, 2000

    • Search Google Scholar
    • Export Citation
  • 29

    Pastorekova S, & Zavada J: Carbonic anhydrase IX (CA IX) as a potential target for cancer therapy. Cancer Ther 2:245262, 2004

  • 30

    Pastorekova S, , Zavada Z, , Kostal M, , Babusikova O, & Zavada J: A novel quasi-viral agent, MaTu, is a two-component system. Virology 187:620626, 1992

    • Search Google Scholar
    • Export Citation
  • 31

    Proescholdt MA, , Mayer C, , Kubitza M, , Schubert T, , Liao SY, & Stanbridge EJ, et al.: Expression of hypoxia-inducible carbonic anhydrases in brain tumors. Neuro Oncol 7:465475, 2005

    • Search Google Scholar
    • Export Citation
  • 32

    Robertson N, , Potter C, & Harris AL: Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 64:61606165, 2004

    • Search Google Scholar
    • Export Citation
  • 33

    Sallinen PK, , Haapasalo H, , Visakorpi T, , Helen PT, , Rantala IS, & Isola J, et al.: Prognostication of astrocytoma patient survival by Ki-67 (MIB-1), PCNA and S-phase fraction using archival paraffin-embedded samples. J Pathol 174:275282, 1994

    • Search Google Scholar
    • Export Citation
  • 34

    Supuran CT, , Briganti F, , Tilli S, , Chegwidden WR, & Scozzafava A: Carbonic anhydrase inhibitors: sulfonamides as antitumor agents?. Bioorg Med Chem 9:703714, 2001

    • Search Google Scholar
    • Export Citation
  • 35

    Swietach P, , Vaughan-Jones RD, & Harris AL: Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 26:299310, 2007

    • Search Google Scholar
    • Export Citation
  • 36

    Teicher BA, , Liu SD, , Liu JT, , Holden SA, & Herman TS: A carbonic anhydrase inhibitor as a potential modulator of cancer therapies. Anticancer Res 13:15491556, 1993

    • Search Google Scholar
    • Export Citation
  • 37

    Wykoff CC, , Beasley NJ, , Watson PH, , Turner KJ, , Pastorek J, & Sibtain A, et al.: Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:70757083, 2000

    • Search Google Scholar
    • Export Citation
  • 38

    Yoo H, , Baia GS, , Smith JS, , McDermott MW, , Bollen AW, & Vandenberg SR, et al.: Expression of the hypoxia marker carbonic anhydrase 9 is associated with anaplastic phenotypes in meningiomas. Clin Cancer Res 13:6875, 2007

    • Search Google Scholar
    • Export Citation
  • 39

    Yoshiura K, , Nakaoka T, , Nishishita T, , Sato K, , Yamamoto A, & Shimada S, et al.: Carbonic anhydrase II is a tumor vessel endothelium-associated antigen targeted by dendritic cell therapy. Clin Cancer Res 11:82018207, 2005

    • Search Google Scholar
    • Export Citation

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